Percutaneous penetration enhancer of oleic acid and 2-ethyl-1, 3-hexanediol

ABSTRACT

Pharmaceutical preparations comprised of a pharmaceutically active ingredient and a carrier which comprises a percutaneous penetration enhancer comprised of 2-ethyl-1, 3-hexanediol alone or in combination with oleic acid is disclosed. The 2-ethyl-1, 3-hexanediol may be present in an amount in the range of about 50% to 100% based on the weight of the carrier. The oleic acid may be used in combination with 2-ethyl-1, 3-hexanediol in an amount of about 1 to 40% based on the weight of the carrier to provide a synergistic effect with respect to percutaneous penetration enhancement. The compound 2-ethyl-1, 3-hexanediol as used alone and/or in combination with the oleic acid has been found to significantly enhance the delivery of a drug, to a patient, from a transdermal delivery system.

FIELD OF THE INVENTION

The present invention relates to the field of pharmaceuticalpreparations which are applied to the skin in order to obtaintransdermal delivery of a pharmaceutically active drug from thepreparation to the patient. More specifically, the invention relates tosuch preparations which utilize as a percutaneous penetration enhancer2-ethyl-1, 3-hexanediol alone and/or in combination with oleic acid.

BACKGROUND OF THE INVENTION

It is well known that many drugs taken orally, are destroyed on thefirst pass through the liver. It is also well known that when many drugsare taken orally, their rate of absorption into the body is notconstant. In view of such difficulties, a number of different drugdelivery systems have been developed. Recently, the use of transdermaldelivery systems have met with increasing interest by researchers in thepharmaceutical drug delivery field.

U.S. Pat. No. 4,291,015 to Keith, et al., discloses the use of apolymeric diffusion matrix for the sustained release of pharmaceuticallyactive drugs. The matrix is covered by a backing layer and applied tothe skin where diffusion of the pharmaceutically active drug occurs andthe drug is transdermaley delivered to the patient. Although U.S. Pat.No. 4,291,015 discloses transdermal delivery of nitroglycerine, otherdrugs may be delivered by utilizing the same or a similar matrix, asdisclosed in U.S. Pat. Nos. 4,292,820; 4,292,302; and 4,292,303.

U.S. Pat. No. 4,490,206 discloses the use of a different type oftransdermal delivery system whereby the pharmaceutically active drug isdispersed within an adhesive (see also U.S. Pat. No. 4,390,520). Inaccordance with such systems, the pharmaceutically active drug isdispersed in a pressure-sensitive adhesive which is adhered to the skin.The drug then diffuses from the adhesive through the skin for deliveryto the patient. Other types of transdermal delivery systems are alsoknown and each has various advantages and disadvantages with respect tothe transdermal delivery of different types of pharmaceutically activedrugs.

One of the problems with utilizing transdermal delivery systems is oneof efficacy. More specifically, the device must supply a sufficientamount of the pharmaceutically active ingredient to the patient toobtain the desired pharmaceutical effect on the patient over a givenperiod of time. Different means may be employed in order to obtain thedesired efficacy over that period of time.

One means of attempting to increase the amount of drug delivery might beto include a higher concentration of the pharmaceutically active drug inthe delivery system. By simply increasing the concentration of the drug,the amount of the drug delivered to the patient would hopefully beincreased. This concept might work well to a certain extent but would belimited by the amount of drug which can be delivered through the skinbarrier, i.e., the skin acts as a rate limitation means.

Another means for increasing the amount of drug delivered and obtainingthe desired efficacy, might involve increasing the surface area contactof the delivery system with the skin. Although an increase in thesurface area will increase the amount of drug delivered to the patient,there are, of course, practical limitations with respect to increasingthis surface area. The cost of producing very large delivery systemsmight be prohibitive. Patients would be unlikely to ware a deliverysystem which had a surface such that it covered the entire back and/orfront of the patient.

A completely different concept for increasing transdermal delivery of apharmaceutically active drug is the utilization of a penetrationenhancer to be used in combination with the drug delivery system.Utilization of such enhancers is subject to certain limitations such asthe fact that the enhancer must be determatologically acceptable, andcompatible with the pharmaceutically active drug as well as the deliverysystem which it is used in connection with.

Perhaps the most famous of such penetration enhancers is "DMSO (Dimethylsulfoxide)". However, DMSO has not received FDA approval for use onhumans. Another well known penetration enhancer is AZONE, see U.S. Pat.Nos. 3,909,816; 4,311,481; and 4,316,893 as well as the correspondingforeign patents.

More recently, there has been some teachings with respect to the use ofoleic acid as a penetration enhancer. (See Cooper, Eugene, R.,"Increased Skin Permeability for LITOTHILIC Molecules" Journal ofPharmaceutical Sciences, volume 73, number 8, August 1984.) Cooperdiscloses the use of oleic acid in different concentrations in thepresence of propylene glycol as a solid. The oleic acid does appear toenhance penetration of the active ingredient SALICYLIC acid. Cooper alsodiscloses the use of oleic acid in combination with 1,2-butanediol. Thearticle specifically indicates that "other diols also exhibit thissynergism with lipids, but the effect is less pronounced as the chainlength is increased". Cooper teaches that the treatment of the skin withsurfactants can have a substantial influence on increasing thepenetration of polar molecules. However, such surfactants do notgenerally increase the transdermal penetration of the non-polarmolecules. Accordingly, Cooper concludes that the enhanced transdermalpenetration of non-polar molecules such as salicylic acid can beobtained by the addition of small amounts of fatty acids or alcohols tothe formulation. More specifically transdermal penetration of salicylicacid can be greatly enhanced by the addition of small amounts of oleicacid. Accordingly, Cooper appears to teach only the use of small amountsof oleic acid either alone or in combination with diols of short chainlength and contains no teachings with respect to the use of largeamounts of oleic acid alone or in combination with long chain diols andactually teaches against the use of such long chain diols.

U.S. Pat. No. 4,305,936 discloses a solution for topical or localapplication comprised of a corticosteroid in a carrier. The carrier iscomprised of 1 to 4% by weight of solubilizing agents of a glyceralester of a fatty acid containing 6 to 22 carbon atoms, 10 to 50% byweight of an alkanol cosolvent and from 20 to 50% by weight of water.The patent also indicates that the carrier can include a carrier a"suitable auxiliary adjuvant in an amount of up to 10% by weight." Oleicacid is mentioned as a suitable auxiliary adjuvant. The patent does notappear to contain any teaching with respect to the effect oleic acidmight have on enhancing penetration and does not appear to contain anyteachings with respect to the use of large amounts of oleic acid aloneor in combination with a long chain diol.

U.S. Pat. No. 4,455,146 discloses a plaster comprised of athermalplastic elastomer, an oil or higher fatty acid, a tack-providingresin and an active ingredient. The "higher fatty acid" may be presentin the range of 25 to 370 parts by weight per 100 parts by weight of thethermalplastic elastomer. The active ingredient may be present in anamount in the range of 0.09 to 110 parts by weight per 100 parts byweight of the thermalplastic elastomer, (see column 4, lines 3-35).Oleic acid is mentioned as "one of the preferred" higher fatty acids,(see column 3, lines 16-17).

Although percutaneous penetration enhancers are known, there remains aneed for an enhancer which is dermatologically acceptable has FDAapproval for use on human skin and has a substantial effect onincreasing in the rate of transdermal delivery of a pharmaceuticallyactive drug to a patient.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical preparation in the formof a transdermal delivery system comprised of a carrier having dispersedtherein a pharmaceutically active drug. The carrier is comprised of apercutaneous penetration enhancer which includes 2-ethyl-1, 3-hexanediol(hereinafter EHD) alone and/or in combination with oleic acid. Thepresent inventor has found that the use of high concentrations of EHD asa carrier can have a substantial effect on increasing in the rate ofdelivery of pharmaceutically active drugs and has further found thatrate of delivery is further enhanced, and a synergistic effect isobtained, when the oleic acid is used in combination with EHD. Thepercutaneous penetration enhancement of this combination has been foundto work particularly well in connection with pharmaceutically activedrugs such as vasodiolators e.g., nitroglycerine, anti-arythmias e.g.,lidocane; sterioids e.g., estrogen and corticosteroids.

It is a primary object of this invention to provide a percutaneouspenetration enhancer for use in connection with a transdermal deliverysystem.

Another object of this invention is to provide such a penetrationenhancer which is comprised of a large percentage of EHD alone and/or incombination with oleic acid.

Still another object of this invention is to provide a transdermaldelivery system using EHD in an amount of 50% to 100% based on theweight of the carrier as a penetration enhancer.

Another object of this invention is to provide a transdermal deliverysystem comprised of a pharmaceutically active ingredient and a carrierwhich carrier is comprised of EHD in an amount of 50% or more by weightand oleic acid in an amount of 1 to 40% by weight based on the weight ofthe carrier.

Yet another object of this invention is to provide a transdermaldelivery system comprised of nitroglycerine and a carrier wherein thecarrier is comprised of 50% or more by weight of EHD and about 5% byweight of oleic acid.

DETAILED DESCRIPTION OF THE INVENTION

In order for a compound to be useful as a percutaneous penetrationenhancer the compound must meet a number of different requirements.Firstly, the compound must be a determatologically acceptable compoundwhich when used topically on the skin does not cause adverse sideeffects. Secondly, the compound must be compatible with the activeingredient within the transdermal delivery system. If the compound andthe active ingredient are incompatible then a separation will take placeor a reaction could occur which would destroy the pharmacologicalactivity of the active ingredient. Thirdly, it is preferable for thecompound to have been approved for use on humans by the Food And DrugAdministration of the United States. Further, the compound must ofcourse have a substantial effect on increasing the transdermal rate ofdelivery of the pharmaceutically active drug.

The present inventor investigated a large number of compounds in orderto find one or more compounds which would meet the above referred tocriteria and be useful as a percutaneous penetration enhancer. One suchcompound investigated was EHD which is known to be useful as an insectrepellent. In addition to being used as an insect repellent, EHD hasbeen used in an antibacterial and an antifungal composition as disclosedby Minuto in U.S. Pat. No. 4,241,084. This patent discloses apharmaceutical composition which includes an antibacterial - antifungalcomposition dispersed in other components which may include EHD. Thecomposition may be applied to the skin for the topical application ofthe antibacterial and antifungal compositions.

Another compound investigated by the present inventor was oleic acid.Oleic acid has been used as a vehicle in which salicylic acid andcarbinoxamine have been incorporated. See "Percutaneous Absorption OfDrugs From Oily Vehicles" Washitake, et al., Journal of PharmaceuticalSciences, volume 64, number 3, pages 397-401. Further, oleic acid hasbeen disclosed as being used in connection with a salicylic acid asindicated above by Cooper. The publication by Washitake, et al.,demonstrates that the effect of oleic acid varies depending on theactive ingredient which is included with the oleic acid. Therefore, itis not possible to accurately predict which pharmaceutically activecompounds might have their skin penetration enhanced by the use of oleicacid.

EXAMPLE 1

Nineteen different compositions were prepared containing 10%nitroglycerine each. The composition of the carrier within each of thenineteen different compositions is shown below in Table I.

                                      TABLE I                                     __________________________________________________________________________    Diffusion of Nitroglycerine Through                                           Hairless Mouse Skin Vehicle Composition, ml.sup.1                             10%                                                                           NTG/PG.sup.2                                                                          PG DET                                                                              DMSO                                                                              DTP                                                                              EHD FSB H.sub.2 O                                                                        OA UREA                                       __________________________________________________________________________     1.                                                                             2     2  2                                                                   2.                                                                             1     4                                                                      3.                                                                             4                                                                            4.                                                                             2     1            1                                                         5.                                                                             2     1  1                                                                   6.                                                                             2     0.5                                                                              1                 0.5   100 mg                                      7.                                                                             2                  1   200 mg                                                                            1                                                 8.                                                                             2                  1.8  55 mg                                                                            0.2                                               9.                                                                             2                  1.8     0.2   410 mg                                     10.                                                                             1     2            1       1                                                  1     1            2       1                                                  1     1            2       1     300 mg                                       1     3                    1                                                  1     1            2   100 mg                                                                            1                                                  1     0.8                     0.2                                             1     0.9                     0.1                                             1     0.7                     0.3                                             1     0.8   0.2                                                               1     0.8       0.2                                                         __________________________________________________________________________     .sup.1 except for the oleic acid experiments when 0.5 ml was used, 1 ml       donor phase was applied to each skin.                                         .sup.2 10% NTG/PG = Lot SDM no. 27, A 274, ICI                                PG = propylene glycol                                                         DET = N,N--diethylm-toluamide                                                 DTP = 1,3dimethyl-3,4,5,6 tetrahydro2(1H) pryimidinone                   

After preparing each of these nineteen different compositions thecompositions were tested to determine the effect of all of the compoundson enhancing the percutaneous penetration of nitroglycerine throughhairless rat skin. The results of these test for all nineteencompositions are shown within Table 11.

                  TABLE II                                                        ______________________________________                                        Mg NTG/skin   Flux.sup.1 ± s.d.                                                                       Lag Time   N                                       ______________________________________                                         1.  0.05         0.044 ± 0.032                                                                            2.7 ± 0.56                                                                         6                                      2.  0.02         0.0074 ± 0.006                                                                          1.86 ± 1.38                                                                         5                                      3.  0.1          0.022 ± 0.003                                                                           1.85 ± 0.28                                                                         4                                      4.  0.05         0.021        2.23     2                                      5.  0.05         0.007        2.57     2                                      6.  0.05         0.010        1.41     2                                      7.  0.05         0.032                 2                                      8.  0.05         0.012                 2                                      9.  0.05         0.012                 2                                     10.  0.02         0.019        1.52     2                                     11.  0.02         0.015 ± 0.005                                                                           1.48 ± 0.47                                                                         6                                     12.  0.02         0.024        1.85     2                                     13.  0.02         0.022 ± 0.003                                                                           1.51 ± 0.06                                                                         4                                     14.  0.02         0.017 ± 0.003                                                                           1.51 ± 0.13                                                                         4                                     15.  0.05         0.306 ± 0.084                                                                           1.11 ± 0.41                                                                         8                                     16.  0.05         0.360 ± 0.089                                                                           1.65 ± 0.46                                                                         6                                     17.  0.05         0.351 ± 0.034                                                                           1.70 ± 0.08                                                                         3                                     18.  0.05         0.032 ± 0.004                                                                           2.84 ± 0.81                                                                         3                                     19.  0.05         0.039 ± 0.019                                                                           2.53 ± 0.23                                                                         3                                     ______________________________________                                         .sup.1 flux measured in mg/cm.sup.2 hr for times up to 10 hours          

The data within Table II clearly shows that the oleic acid utilized asthe percutaneous penetration enhancer in compositions 15, 16, and 17greatly increased the flux through the hairless mouse skin.

EXAMPLE 2

After determining that oleic acid had a substantial influence onenhancing the penetration of nitroglycerine through hairless mice skinthe present inventor had experiments carried out in order to determinethe amount of oleic acid which could be utilized in order to mostefficiently enhance the penetration. The results of those experimentsare summarized in Table III.

                  TABLE III                                                       ______________________________________                                        Oleic Acid Concentration In Vehicle:                                          Nitroglycerine Flux through Hairless Mouse Skin                               Oleic Acid     Flux, mg/cm.sup.2 hr                                                                       n                                                 ______________________________________                                         0             0.046 ± 0.021                                                                           9                                                  5             0.360 ± 0.089                                                                           6                                                 10             0.306 ± 0.084                                                                           8                                                 15             0.351 ± 0.034                                                                           3                                                 ______________________________________                                    

The results shown within Table III indicate that the flux of thenitroglycerine across the hairless mouse skin is not increased much byincreasing the amount of oleic acid beyond 5% by weight based on thetotal weight of composition.

After determining the usefulness of oleic acid as a percutaneouspenetration enhancer the present inventor carried out experimentation inorder to determine if the combination of two or more different compoundsmight have some synergistic effect with respect to enhancing penetrationof one or more active ingredients. As a result, the present inventor didfind that the addition of minor amounts of oleic acid to major amountsof EHD had a synergistic effect with respect to the percutaneouspenetration enhancement of pharmaceutically active ingredients.Information describing experiments and the results obtained were putforth below.

EXAMPLE III Diffusion of Triamcinolone Acetonide Through Hairless MouseSkin

Solutions of Triamcinolone Acetonide (TA) (RD-2K-0537) in propyleneglycol (PG), 2-ethyl, 1,3 hexanediol (EHD), and 5% oleic acid (OA) inEHD were used to measure the flux in mg/cm² hr of the compound throughhairless mouse skin. When a 0.5% solution of the compound in 5% OA/EHDwas applied, the flux was about four times greater than that from a 0.5%solution in PG and twice that of a 0.5% solution in EHD. Similarly, 5%OA/EHD was almost twice as effective as EHD alone when a 0.1% solutionwas used. This solvent gave results about twelve times better than PGalone at this concentration.

Experimental

Skins from female hairless mice, strain SKH1HR-1 (Temple University)were placed over circular teflon holders and secured with O-rings. Theholders were attached to Plexiglas reservoirs filled with a receptorphase consisting of 39 ml of 2% Brij 58 (polyoxethylene 20 cetyl either,Sigma) dissolved in pH 7.4 isotonic phosphate buffer and 0.4 mlformalin. The solution was degassed before use. 500 l aliquots of thetest solutions were spread over each skin. The diffusion cells werestirred for 48 hrs in a 35° incubator and 1 ml samples were removed atintervals and frozen until analyzed.

The samples were analyzed by HPLC using a Waters 481 variable wavelengthUV detector set at 20 nm, LDC constametric III pump at 1 ml/min flow,and Fisher Recordall recorder at chart speed 0.25 cm/min. Using a C-18column and 50% acetonitrile in distilled water triamcinolone had aretention of 1.4 cm.

                  TABLE IV                                                        ______________________________________                                        Results                                                                       The Flux of TA in Each of Three Solvents                                               0.1% TA      0.5% TA                                                 ______________________________________                                        PG         2.04 + 1.4 × 10.sup.-5                                                                 2.49 + 0.88 × 10.sup.-4                       EHD        1.49 + 0.39 × 10.sup.-4                                                                5.35 + 2.00 × 10.sup.-4                       5% OA/EHD  2.57 + 0.56 × 10.sup.-4                                                                1.06 + 0.39 × 10.sup.-3                       ______________________________________                                    

Diffusion of Estradiol Through Hairless Mouse Skin

Estradiol was mixed with an assortment of diffusion enhancing substancesin an attempt to increase its flux through skin. The compound was alsomixed with its ester, estradiol 17- cypionate, to achieve the sameresult. Since estradiol is not especially water soluble the receptorphase was varied to include different amounts of a surfactant or plasmato better dissolve any diffused estradiol which might be attached to theunderside of the skin.

Experimental

Female hairless mice, strain SKHI-R-1 (Temple University) were killed bycervical dislocation. The skins were removed, placed carefully over acircular teflon holder, and held in place with an O-ring. This yielded a7.07 cm² skin surface which was suspended over a plexiglas reservoir(Kersco Engineering, Palo Alto, Calif.) containing 39 ml of receptorphase: ph 7.4 phosphate buffer with or without 2% Brij-58(polyoxyethylene 20 cetyl ether) or plasma. The receptor phase wasfiltered under a vacuum to remove dissolved air. Estradiol 100 mg, or100 mg estradiol plus 100 mg estradiol 17- -cypionate, was powdered andmixed with 2 ml of the desired vehicle. The resulting suspension wassonicated and 0.5 ml spread over each skin. The cells were stirredovernight in a 35° C. incubator and 1 ml samples taken at 6 hrintervals. Samples were pipetted into 1 ml CH₃ CN to dissolve alldiffused estradiol.

The samples were analyzed by HPLC using a Beckman model 160 detector at280 nm. Mobile phase was 55% CH₃ CN in distilled water. At a flow of 1ml/min and chart speed 0.5 cm/min estradiol retention was 2.95 cm.

Results:

Table I summarizes 33 experiments using estradiol alone mixed withdifferent combinations of 15 vehicle additives. Fair results wereobtained with vehicles which contained 2-ethyl-1,3-hexanediols (EHD) or,N,N'-diethyl-m-toluamide (DET) and oleic acid (OA) or methyl salicylate(m-Sal); total flux through skin was 1.1-1.6×10⁻³ mg/cm hr.

Several experiments were conducted using a combination of estradiol andits 17- cypionate ester using combinations of nine vehicle additives(Table 2). Total flux was not changed dramatically over that found whenestradiol alone was used. The flux of estradiol observed when estradiol17- cypionate alone was applied to skin was considerably lower (TableIII).

The results using different receptor phases are shown in Table IV. Noneof the conditions are significantly different from the others.

Conclusion:

Using DET, EHD, m-Sal or OA in the vehicle seems to give best resultsfor the diffusion of estradiol through hairless mouse skin. Attempts toincrease the flux by adding an ester to the donor phase or by making thereceptor phase more lipophilic were not successful.

                                      TABLE V                                     __________________________________________________________________________    Vehicle Composition and Flux of Estradiol through Skin                        after Application of Estradiol-Estradiol Cypionate Mixture                    % of Vehicle.sup.1                                                            DET                                                                              DMSO                                                                              DTP                                                                              EHD IPM                                                                              OA m-Sal                                                                             MO PMS                                                                              Flux, mg/cm hr                                                                          N                                     __________________________________________________________________________              100                 1.49 × 10.sup.-3 ± 0.4                                                         17                                              95      5           9.23 × 10.sup.-4 ± 0.24                                                        9                                               90     10           2.15 × 10.sup.-3 ± 0.23                                                        3                                               75     25           1.27 × 10.sup.-3 ± 0.12                                                        3                                               60     40           1.36 × 10.sup.-3 ± 0.81                                                        3                                               57     43           6.08 × 10.sup.-4 ± 0.39                                                        12                                              40     60           1.14 ×  10.sup.-3 ± 0.17                                                       3                                     33            50    17        3.22 × 10.sup.-4 ± 1.12                                                        8                                        10     90                  7.68 × 10.sup.-4 ± 1.14                                                        6                                            10 90                  9.89 × 10.sup.-4 ± 0.16                                                        5                                               95               5  1.41 × 10.sup.-3 ± 0.62                                                        6                                                             100    2.9 × 10.sup.-5 ± 3.03                                                        3                                                             50    4.29 × 10.sup.-4 ± 0.81                                                        3                                               45   5        50    1.34 × 10.sup.-3 ± 0.06                                                        3                                     __________________________________________________________________________     .sup.1 DET, N,N.sup.1 diethylm-toluamide                                      DMSO, dimethyl sulfoxide                                                      DTP, 1,3dimethyl-3,4,5,6 tetrahydro2(IH)pyrimidinone                          EHD, 2ethyl-1,3-hexanediol                                                    IPM, isopropyl myristate                                                      OA, oleic acid                                                                m-Sal, methyl salicylate                                                      MO, mineral oil                                                               PMS, polymethionine sulfoxide                                            

The present inventor determined that oleic acid could not be utilized inconnection with pharmaceutically active ingredients which ingredientswere a base. Accordingly, the present inventor carried out experimentsin order to test the ability of EHD on enhancing the penetration of apharmaceutically active ingredient which acted as a base such as localanesthetics. The results of these experiments are shown below withinExample 4.

EXAMPLE 4

                                      TABLE VI                                    __________________________________________________________________________    Local Anesthetics: Experimental Conditions                                               % of Vehicle.sup.3                                                                                10 N    Vol #                                  Exp.                                                                             Drug                                                                              mg on                   KOH/    App.                                                                              of                                 #  mg.sup.1                                                                          skin                                                                              IPM                                                                              n-p                                                                              PG DEA DET                                                                              EDH MEOH Sal                                                                              ml* ani.                               __________________________________________________________________________    L-1                                                                              39.3.sub.L                                                                        5.24                                                                              100.sup.2                   .20 4                                  L-2                                                                              136.sub.L                                                                         34.0                                                                              67           33             .15*                                                                              4                                  L-3                                                                              151.5.sub.E                                                                       37.9                                                                              67           33             .15*                                                                              2                                  L-4                                                                              155.6.sub.B                                                                       38.9                                                                              67           33             .15 2                                  L-5                                                                              200.9.sub.E                                                                       50.2   34    33  33             .15 2                                  L-6                                                                              204.5.sub.B                                                                       27.9   64    18  18             .15 2                                  L-7                                                                              152.sub.E                                                                         45.6      100                   .18 2                                  L-8                                                                              128.6.sub.B                                                                       38.6      100                   .18*                                                                              2                                  L-9                                                                              206.8.sub.B                                                                       41.4      43        43  14      .18 3                                  L-10                                                                             205.1.sub.E                                                                       52.7      43        43  14      .18 3                                  L-11                                                                             406.3.sub.E                                                                       110.8     38        38   8   15 .3  4                                  L-12                                                                             428.7.sub.B                                                                       98.9      38        38   8   15 .3  4                                  L-13                                                                             207.1.sub.E                                                                       53.3                86  14      .18 3                                  L-14                                                                             208.8.sub.B                                                                       53.7                86  14      .18 3                                  __________________________________________________________________________     .sup.1 B, Bupivacaine.HCl                                                     E, Etidocaine.HCl                                                             L, Lidocaine.HCL.H.sub.2 O                                                    .sup.2 10% IPM in acetone                                                     *suspension                                                                   .sup.3 IPM, isoprypyl myristate                                               n-p, normal propanol                                                          PG, propylene glycol                                                          DEA, diethanolamine                                                           DET, N,N--diethylm-toluamide                                                  EHD, 2ethyl-1,3-hexanediol                                                    KOH/MeOH, potassiumhydroxide/methanol                                         m-Sal, methyl salicylate                                                 

                  TABLE VII                                                       ______________________________________                                        Local Anesthetics: Results                                                    Exp.                                                                          #       Flux ± S.D. mg/cm.sup.2 hr                                                                 Lag time ± S.D., hrs                               ______________________________________                                        L-12    9.67 ± .295 × 10.sup.-1                                                              5.6 ± 0.2                                          L-11     4.7 ± .179 × 10.sup.-1                                                              3.8 ± 1.6                                          L-9     1.46 ± 0.01 × 10.sup.-1                                                              6.5 ± 0.2                                          L-3     1.43 × 10.sup.-1                                                                        3.2                                                   L-10    6.97 ± 0.49 × 10.sup.-2                                                              6.6 ± 0.1                                          L-2     5.62 ± 0.01 × 10.sup.-2                                                              2.9                                                   L-14    3.09 ± 1.46 × 10.sup.-2                                                              9.1 ± 0.2                                          L-13    2.66 ± 0.65 × 10.sup.-2                                                              6.3 ± 0.1                                          L-4     1.55 × 10.sup.-2                                                                        4.3                                                   L-6     1.45 × 10.sup.-2                                                                        5.2                                                   L-7     4.14 × 10.sup.-3                                                                        6.4                                                   L-8     3.15 × 10.sup.-3                                                                        5.2                                                   L-5     1.01 × 10.sup.-3                                                                        3.4                                                   L-1     4.65 ± 0.1 × 10.sup.-4                                                               0                                                     ______________________________________                                    

Further experimentation was then carried out in order to test theability of certain compounds to enhance the penetration of estradiol.The results of these experiments are put forth below in Table III.

                                      TABLE VIII                                  __________________________________________________________________________    Vehicle Composition and Flux of Estradiol through Skin                        % of Vehicle or mg solid added.sup.1                                                    Brij                                          Flux, mg/             IPM                                                                              n-P PG 58   DEA DET DOS  EHD H.sub.2 O                                                                         FSB OA m-Sal                                                                             SLS  Urea                                                                              cm.sup.2              __________________________________________________________________________                                                            hr                    67                 33                                    1.4 ×                                                                  10.sup.-6             50                 33                      17           1.51 ×                                                                  10.sup.-3             50                          50                          4.27 ×                                                                  10.sup.-4             57                                      43               3.8 ×                                                                  10.sup.-4             50                                         17            1.3 ×                                                                  10.sup.-3                100                                                   1.4 ×                                                                  10.sup.-4             50                                         17           1.16 ×                                                                  10.sup.-3                75              25                                   4.93 ×                                                                  10.sup.-4                70              30                                    1.2 ×                                                                  10.sup.-3                50              50                                   6.59 ×                                                                  10.sup.-4                25              75                                   6.66 ×                                                                  10.sup.-4                80          20                                       1.29 ×                                                                  10.sup.-4                50                                                   4.62 ×                                                                  10.sup.-4                25          25  25                                   4.52 ×                                                                  10.sup.-4                40          20  40                                   5.88 ×                                                                  10.sup.-4                48           5  47                                   4.26 ×                                                                  10.sup.-4                50     75.4 mg           50                          1.43 ×                                                                  10.sup.-4                50                  118.4 mg                                                                           50                          2.14 ×                                                                  10.sup.-4                50                       50                 39.6 mg  6.96 ×                                                                  10.sup.-5                    50                   50                          4.62 ×                                                                  10.sup.-4                    57                               43              8.36 ×                                                                  10.sup.-4                23  23          38           15                  100                                                                               4.47 ×                                                                  10.sup.-4                20  34                   33  13  50 mg               2.32 ×                                                                  10.sup.-4                20  34          33           13  50 mg               3.67 ×                                                                  10.sup.-4                23  23                   38  15                  100                                                                               5.22 ×                                                                  10.sup.- 5                               100                                   2.5 ×                                                                  10.sup.-4                                                     100             5.55 ×                                                                  10.sup.-4                                                     100             8.23 ×                                                                  10.sup.-4                                29                   71              6.18 ×                                                                  10.sup.-4                                57                   43              1.59 ×                                                                  10.sup.-3                                         29          71               9.0 ×                                                                  10.sup.-4                                         57          43              6.38 ×                                                                  10.sup.-4                                33                   50 17           1.05 ×                                                                  10.sup.-3             __________________________________________________________________________     .sup.1 IPM, isopropyl myristate                                               n-P, normal propanol                                                          PG, propylene glycol                                                          Briji-58, polyoxyethylene 20 cetyl ether                                      DEA, diethanolamine                                                           DET, N,N--diethylm-toluamide                                                  DOS, dioctysulfosuccinate                                                     EHD, 2ethyl-1,3-hexanediol                                                    FSB, formaldehyde sodium bisulfite                                            OA, oleic acid                                                                m-Sal, methyl salicylate                                                      SLS, sodium lauryl sulfate                                               

The results shown within Table VIII clearly indicate that oleic acid andEHD can increase the flux of estradiol through skin.

The present invention has been disclosed and described herein in what isbelieved to be its preferred embodiments. It is recognized, however,that those skilled in the art may contemplate variations thereof whichare not specifically disclosed herein, which variations are intended tobe encompassed by the scope of the present invention. Accordingly, thescope of the present invention should not be construed as being limitedto the above description.

What is claimed:
 1. A transdermal delivery system, consistingessentially of:nitroglycerine; and a carrier which consists of 1 to 10%by weight of oleic acid based on the weight of the carrier.